Substance libraries

Recently, a solid-phase synthesis was used iteratively for the synthesis of organic substances like oligocarbamates [13] and oligoureas [14] by repeated coupling to amino-functionalized supports. In this way substance libraries [15] have been developed showing that iterative methods can also be employed in combinatorial chemistry [16]. 

One very important aspect in modern drug discovery is the preparation of so-called substance libraries from which pharmaceutical lead structures might be selected for the treatment of different diseases. An efficient approach for the preparation of highly diversified libraries is the development of multicomponent reactions, which can be defined as a subclass of domino reactions. One of the most... 

In recent years, synthetic methodology has been developed to allow the synthesis of diversified substance libraries mainly for pharmaceutical testing in an automated way using either solid phase or solution chemistry.121 Here, efficiency is also an important goal. 

In addition, synthetic methodology must be designed in a way that allows access to diversified substance libraries in an automated way [2]. Though solid-phase chemistry is now of a high standard for use in combinatorial chemistry, solution chemistry retains several advantages. 

Solid-phase methodology was established in 1963 in pioneering work conducted by Merrifield in the area of peptide synthesis [19]. Interest in this synthetic strategy continues unabated to this day, particularly in connection with the production of new active components for drugs, since the repetitive amide bond formation performed in automated synthesisers lends itself ideally to the construction of extensive substance libraries by combinatorial chemistry [20]. 

Fig. 5.10 3-Substituted coumarin derivatives 26 with high fluorescence quantum yields identified by screening of substance libraries.

An anchor for traceless linking might also have a safety-catch function or be suitable for multifunctional cleavage. Linker systems enable the introduction of certain atoms or molecule fragments and will play an important role in the development of diverse organic substance libraries. It is important to point out that the final diversity is achieved on cleavage, and not in an additional solution phase re-... 

The key goal of any HTS is to discover as many meaningful hits as possible from a compound collection while achieving an acceptable false positive rate. This requires careful consideration of factors such as the nature of the target, an appropriate substance library, and an assay predictive of all possible interactions of an unknown compound with the target of interest. 

In hit finding, a large number of compounds, the so-called library, is screened v. a target to identify components that bind. Libraries can meet different types of requirements, and efforts are made to optimize them with respect to diversity, solubility, drug-like character (see Table 1), and the synthetic accessibility of the compounds they contain. Substance libraries can contain small organic fragments, synthetic compounds of diverse chemical structures, or natural products. ... 

The total synthesis of ZK-EPO (1) is an example of a highly convergent synthesis which contains the construction and combination of three segments. The segments are built up by reactions that allow and tolerate the introduction of different substituents and are suitable for the construction of substance libraries. This was necessary both for toxicity and structure-response relationship studies. Note that 1 was developed via this library synthesis. 

The electrochemical robotic system was first applied for characterization of a combinatorial substance library.67 256 quarter (3-arylthiophenes) were screened by means of cyclic voltammetry to reveal their redox properties. The first oxidation potentials leading to the formation of the radical cation of the investigated species could be correlated with the electronic effects of the individual substituents (Fig. 14.18). 

Based on a AChE inhibitor with a 1,4-substituted 4-(lH)-pyridylene-hydrazone skeleton, Prinz et al. [184] generated a substance library for inhibition of AChE, BChE, and Ap fibril formation. A bisnaphthyl-substituted compound was found to be the best overall inhibitor of AChE/BChE, with capacity for Ap fibril destruction. 

When effect mechanisms and targets have been identified, combinatorial screening methods using substance libraries fish out the molecules from the thousands of possible molecule combinations. The best molecule then serves as the basic structure, which can be further optimized and finally synthesized at large scale. 

Automated combinatorial chemistry has, over the past ten years, firmly established itself as an autonomous chemical discipline. Ensembles of highly diverse compounds in the substance libraries of the chemical industry constitute a valuable reserve for developing new active substances. 

Bureau of Toxic Substances Library Virginia Department of Health 1500 E. Main Street, Room 124 Richmond, VA 23219 Phone (804) 786-1763 Fax (804) 786-9510... 

G. Quinkert, A. Eschenmoser, Novel substance library and supramolecular complexes produced therewith, PCT Int. Appl. WO 97/43232. Chem. Abstr. 

To summarize, a lot of work has been done in the field of fluorination reactions in microfluidic devices. Concerning the deoxofluorination with hazardous DAST, the development of a process from laboratory to pilot plant scale with inline process analysis was nicely demonstrated. Later on, the scope of substrates and fluorinating agents was broadened and inline purifications were introduced on laboratory scale. Thus, the microfluidic devices were a good tool to establish substance libraries. In the case of radiolabeling with [ F] fluoride ions, the chapter focused on recent advances in continuous-flow microfluidic procedures. However, the miniaturization for a continuous processing of all necessary preparation steps remains a major challenge. 

Interesting developments originate from experiments that use the trNOE effect to screen substance libraries for binding activity against receptor proteins. The first attempts to perform such bio-affinity protocols were rather successful [77, 78], and recently a new experimental strategy was introduced that allows a very robust and powerful screening of libraries, called STD-NMR [79, 80], The new method is based on the principle of saturation transfer and can be combined with virtually any other NMR technique. Whereas trNOE experiments are well established tools to study bioactive conformations, especially of carbohydrate ligands, the use of bio-affinity NMR methods is still in its infants and promises more surprises in the near future. 

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